While cardiovascular disease is the leading cause of death in both men and women in the United States, it is only after menopause that the risk of developing congestive heart failure dramatically increases in women. The proposed study will investigate gender-specific differences in myocardial remodeling and the development of heart failure secondary to chronic volume overload. Specifically, the focus of this proposal will be estrogen's modulation of TNF-alpha production and release from cardiac mast cells. The overall hypothesis to be examined is that estrogen modulation of TNF-alpha is responsible for the gender differences in cardiovascular remodeling induced by chronic volume overload. To this end, the following specific aims will be addressed using a variety of physiological, biochemical, morphological and molecular techniques to delineate the mechanisms responsible for the gender-specific differences in cardiovascular function and the temporal progression of adverse ventricular remodeling induced secondary to either infrarenal aortocaval fistula or TNF-alpha infusion in rats. Aim 1: Does estrogen alter the dynamic remodeling process induced by chronic volume overload? Aim 2: What role does the estrogen modulation of TNF-alpha play in myocardial remodeling and development of heart failure? Aim 3: Is estrogen modulation of mast cell-derived TNF-alpha the mechanism responsible for cardioprotection observed in intact females? In summary, the proposed studies will provide a well integrated approach designed to fill a void in our understanding of the mechanisms responsible for the cardioprotection observed in premenopausal females. We have every expectation that the investigations will significantly increase our understanding of the important interactions between estrogen, cardiac mast cell-derived TNF-alpha, cardiac fibroblasts, myocytes, and the extracellular matrix during cardiovascular remodeling secondary to chronic volume overload and advance the development of novel therapeutic approaches for the prevention of heart failure. [unreadable] [unreadable]